Parasiticide



United States Patent M 3,218,339 PARASITICIDE Franklin W. Short andEdward F. Elslager, Ann Arbor, Mich., assignors t0 Parke, Davis &Company, Detroit, Mich., a corporation of Michigan No Drawing. Originalapplication Mar. 24, 1959, Ser. No. 801,444, now Patent No. 3,057,776,dated (let. 9, 1962. Divided and this application Aug. 22, 1962, Ser.No. 218,570

2 Claims. (Cl. 260-391) The present invention relates to novel salts ofpararosaniline and pamoic acid, to methods for their production, and topharmaceutical compositions containing the same.

In our copending application, Serial No. 801,444, filed March 24, 1959now issued as US. Patent 3,057,776, of which the present application isa division, the method for the treatment of schistosomiasis by theadministration of pararosaniline or a suitable derivative thereof wasdisclosed.

It is an object of the present invention to provide novel pararosanilinesalts having high anti-schistosomiasis activity with substantiallyreduced incidence of gastrointestinal side effects when compared withsimple pararosaniline derivatives known to the prior art.

In accordance with the invention, this object, as well as others, whichwill appear hereinafter, is realized by the production of novel salts ofpararosaniline with pamoic acid, otherwise known as 2,2-dihydroxy-1,1-dinaphthylmethane-3,3'-dicarboxylic acid.

According to the invention, the pararosaniline salts of pamoic acid canbe formed by reaction of a soluble salt of pararosaniline with a solublesalt of pamoic acid, suitably in an unreactive medium such as water oran aqueous alkanol. The desired pamoate salt either precipitates fromthe reaction mixture, or can be obtained by concentration of themixture, or by dilution with water or with a non-polar solvent.

In another method for the production of pararosaniline salts of pamoicacid, pararosaniline is treated with pamoic acid, suitably in anun'reactive, approximately neutral solvent such as dimethylformamide oran aqueous alkanol.

The novel salts of pararosaniline and pamoic acid, which are the objectsof this invention, are particularly advantageous for use inanti-schistosomal compositions. Whereas simple pararosaniline salts suchas the hydrochloride do not exhibit the high degree of toxicity shown byprior art compounds used in the treatment of schistosomiasis, theynevertheless exhibit a certain degree of gastrointestinal irritation,including in some subjects vomiting, diarrhea and loss of appetite.These incidental effects of pararosaniline therapy are substantiallyreduced with the novel salts of the invention comprising thetris(p-aminophenyl)carbonium cation (pararosaniline cation) and an anionof pamoic acid. Such salts include bispararosaniline pamoate, a saltcomprising two moles of the pararosaniline cation to one mole of thedivalent pamoate anion, and pararosaniline acid pamoate, a saltcomprising one mole of the pararosaniline cation to one mole of themonovalent acid pamoate anion. These salts produce an antischistosomaleffect upon oral administration with a much lower incidence ofgastrointestinal irritation and toxicity. Moreover, they display reducedstaining properties when compared with simple pararosaniline salts suchas the hydrochloride.

Further, according to the present invention, schistosomacidalcompositions are produced by formulating compositions comprising a saltof pararosaniline with pamoic acid. Such compositions are constituted indosage unit form with pharmaceutical carriers or diluents. In

3,218,339 Patented Nov. 16, 1965 view of the oral activity of thesesalts of pararosaniline, dosage unit forms for oral administration areparticularly suitable. For this purpose, the pararosaniline salt can beincorporated into tablets, powders, capsules, solutions, suspensions andsimilar forms. The medicament can be incorporated with pharmaceuticallyacceptable solid or liquid diluents. Solid carriers and diluents areparticularly suitable for use and include sugars such as lactose andsucrose; cellulose derivatives such as sodium carboxymethyl cellulose,ethyl cellulose, methyl cellulose and cellulose acetate phthalate;gelatin (including hard and soft gelatin capsules); talc; corn starch,stearic acid and magnesium stearate. Liquid carriers and diluentssuitable for use include vegetable oils such as peanut oil, cottonseedoil, seasame oil, olive oil, corn oil, and oil of theobroma;polyethylene glycol; propylene glycol; glycerin; sorbitol; ethanol andwater. Suitable preservatives and flavoring agents can also beincorporated in such compositions. In the production of dosage formssuch as tablets, the use of an enteric coating or a sugar coating isalso useful in minimizing a tendency toward nausea or staining. Ifadministration by a parenteral route is desired, the medicament can alsobe prepared in solution or suspension in ampoule form by admixture witha liquid diluent. Other therapeutic agents can also be incorporated withthe pararosaniline salt in these compositions.

The percentage of the pararosaniline salt in the compositions can bevaried within wide limits, but, for practical purposes, is preferablypresent in a concentration of at least 5%. The most satisfactorycompositions are those in which a much higher proportion of thepararosaniline salt is present.

In the preparation of dosage unit forms such as tablets and capsules thequantity of medicament furnished by each individual tablet or capsule isselected such that the proper total daily dose, falling within the rangeof approximately 0.5 to 4.0 g. (calculated as pararosaniline cationequivalent), can be reached by administering either one or a reasonablenumber of the tablets or capsules. For convenience in manufacturing andease of administration, it is preferable that such dosage forms containat least 50 mg. and up to 500 mg. of pararosaniline compound (calculatedas pararosaniline cation equivalent) per unit.

As previously indicated, the substances and compositions of theinvention are orally effective in the treatment and prophylaxis ofschistosomiasis. They are active against immature as well as matureschistosomes, whereas certain prior art materials have been reportedineffective against immature worms. Moreover, the substances andcompositions of this invention are effective against other trematodes.They are useful in the treatment of paragonimiasis, effecting a stronginhibition in the production of ova in the latter disease.

The invention is illustrated by the following examples:

Example 1 A mixture of 235 g. of pararosaniline hydrochloride(containing 1.8% of water) and g. of disodium pamoa-te monohydrate in 3liters of methanol is heated and stirred for 3 hours and then filteredslowly with vigorous stirring into 15 liters of water. The insolubleproduct is washed with water and dried in vacuo at 50- 60 C. The productobtained in this manner is hydrated bispararosaniline pamoate, a saltcomprising two moles of the tris(p-aminophenyl)carbonium cation(pararosaniline cation) to one mole of the divalent pamoate anion; M.P.about 220225 C.

Example 2 A filtered solution of 11.5 g. of pararosaniline hydrochloridein 200 ml. of water heated to the boiling point 3 is added to a hot,filtered solution of 8.0 g. of disodium pamoate monohydrate in 100 ml.of Water. The gummy product which precipitates solidifies on cooling andis collected on a filter. It is resuspended in Water, again collectedand then dried in vacuo at 50 C. This compound is hydratedbispararosaniline pamoate, substantially identical with the product ofthe preceding example.

Example 3 To a hot, filtered solution of 3.88 g. of pamoic acid in 150ml. of N,N-dimethylformamide is gradually added a solution of 6.10 g. ofpararosaniline in 100 ml. of hot N,N-dimethylformamide. The resultingdeeply-colored solution is heated for one hour at 90100 C. and thenpoured with stirring into 1 liter of cold water. The insoluble productis collected on a filter, washed with Water and dried in vacuo. Thiscompound is dark-green bispararosaniline pamoate, substantiallyidentical With the product of the preceding examples.

Example 4 To a hot, filtered solution of 3.88 g. of pamoic acid in 125ml. of N,N-dimethylformamide is added a solution of 3.05 g. ofpararosaniline in 50 ml. of hot N,N- dimethylformamide. A dark-redsolution which results is heated for one hour at 90100 C. and thenpoured With vigorous stirring into 2 liters of cold water. Thereddish-brown product is collected on a filter, washed well with waterand dried in vacuo at 45 C. Purification by recrystallization frommethanol affords pararosaniline acid pamoate, a salt comprising one moleof the tris(p-aminophenyl) carbonium cation (pararosaniline cation) toone mole of the monovalent acid pamoate anion; M.P. 205-210 C.

Example 5 A batch of hydrated bispararosaniline pamoate is prepared fortableting by treating it with 1% of mineral oil in order to minimizedust formation. This product oil is blended with 800 g. of sifted cornstarch and the mixture wet granulated with a 10% W./w. solution of 176g. of sifted corn starch in distilled Water. After the granulation hasbeen dried and reduced, there are blended in 80 g. of sifted talc, 280g. of sifted corn starch and 14 g. of magnesium stearate. The mixture isthen compressed on a tableting machine to provide about 9500 tablets,each containing approximately 100 mg. of pararosaniline cationequivalent. If desired, a light sugar coating is applied.

A quantity of pararosaniline acid pamoate affording an equal amount ofpararosaniline cation can be substituted for the bispararosanilinepamoate in the foregoing procedure.

We claim:

1. Pamoic acid salt of pararosaniline.

2. Bispararosaniline pamoate.

References Cited by the Examiner UNITED STATES PATENTS 2,641,610 6/1953Barber 260501 2,731,470 l/1956 Elslager 260-295 2,925,417 2/1960Elslager 260'24O 3,067,242 12/ 1962 Larrabee 260501 FOREIGN PATENTS744,281 2/ 1956 Great Britain.

OTHER REFERENCES Deschiens, Chem. Abst., vol. 39, p. 2566(3), 1945.Osol, Dispensatory of U.S., 1955, Part 1, p. 591. Steck, J.A.C.S., vol.70, p. 1012-1015.

Steck, J. A. Pharm. Ass0c., Second Edition, vol. 41, p.

(1828 g.) containing 7.5% of water and 1% of mineral JULIAN S. LEVITT,Primary Examiner.

MORRIS O. WOLK, Examiner.

1. PAMOIC ACID SALT OF PARAROSANILINE.